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I?B Kinase ? Is an NFATc1 Kinase that Inhibits T Cell Immune Response.

ABSTRACT: Activation of nuclear factor of activated T cells (NFAT) is crucial for immune responses. IKK? is an I?B kinase (IKK)-related kinase, and the function of IKK? remains obscure in T cells, despite its abundant expression. We report that IKK? inhibits NFAT activation and T cell responses by promoting NFATc1 phosphorylation. During T cell activation, IKK? was transiently activated to phosphorylate NFATc1. Loss of IKK? elevated T cell antitumor and antiviral immunity and, therefore, reduced tumor development and persistent viral infection. IKK? was activated in CD8(+) T cells of mice bearing melanoma or persistently infected with a model herpesvirus. These results collectively show that IKK? promotes NFATc1 phosphorylation and inhibits T cell responses, identifying IKK? as a crucial negative regulator of T cell activation and a potential target for immunotherapy.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5293007 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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IκB Kinase ε Is an NFATc1 Kinase that Inhibits T Cell Immune Response.

Zhang Junjie J Feng Hao H Zhao Jun J Feldman Emily R ER Chen Si-Yi SY Yuan Weiming W Huang Canhua C Akbari Omid O Tibbetts Scott A SA Feng Pinghui P

Cell reports 20160623 2

Activation of nuclear factor of activated T cells (NFAT) is crucial for immune responses. IKKε is an IκB kinase (IKK)-related kinase, and the function of IKKε remains obscure in T cells, despite its abundant expression. We report that IKKε inhibits NFAT activation and T cell responses by promoting NFATc1 phosphorylation. During T cell activation, IKKε was transiently activated to phosphorylate NFATc1. Loss of IKKε elevated T cell antitumor and antiviral immunity and, therefore, reduced tumor dev ...[more]

PMID: 27346349

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Project description:Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

Dataset Information

I?B Kinase ? Is an NFATc1 Kinase that Inhibits T Cell Immune Response.

Publications

IκB Kinase ε Is an NFATc1 Kinase that Inhibits T Cell Immune Response.

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